Miastenia gravis

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Miastenia gravis

  1. 1. Miastenia Gravis actualización Dr. Juan Lozano
  2. 2. Thomas Willis (1621-1675), English physician, published a book, De anima brutorum (1) in 1672 in which he wrote about "a woman who temporarily lost her power of speech and became 'mute as a fish. '"(1) This has been interpreted as being the first written description of myasthenia gravis. Thomas Willis was born in Great Bedwin, a Wiltshire village in England. He graduated from Oxford University Legion with a Bachelor of Medicine in 1646. In 1660 he was appointed Sedleian Professor of Natural Philosophy at Oxford and given the M.D.(2)
  3. 3. Her first patient, 'Mrs. M.', had had intermittent weakness for 14 years and had been admitted to St. Alfege's Hospital about 2 months prior to the treatment given by Dr. Walker because of an exacerbation. Mrs. M's muscle power was restored about 30 mins after the hypodermic injection of physostigmine sulphate (gr. 1/60) --- the effect lasted up to 4 hours. The case was written up in the Lancet 2nd June 1934, pp. 1200-1 and was also reported in the local newspaper The Kentish Mercury on 15th March 1935. Dra. Mary Walker
  4. 4. Paciente de la Dra Walker 'Mrs. M.' before (left image) and after (right image) injection of physostigmine. Before - patient cannot raise left eyelid. After - eye is fully open. These photos were reproduced from a cine film and appeared in reverse (right for left) in The Lancet 1934 (i) 1200-1. They are reproduced here with correct orientation.
  5. 5. GENTE FAMOSA CON MG <ul><li>David Niven </li></ul><ul><li>Aristotle Onassis </li></ul><ul><li>Sir Lawrence Olivier </li></ul><ul><li>Phil Silvers (actor - Sgt. Bilko) </li></ul><ul><li>&quot;Sleepy&quot; (© Disney) of Snow White and the Seven Dwarfs was supposedly based on a friend of Walt Disney who had MG </li></ul>
  6. 7. Julie Long artista Jerry lewis
  7. 8. Epidemiología <ul><li>Incidencia: 10 x millón x año </li></ul><ul><li>Prevalencia: 14 x 100,000 habitantes </li></ul><ul><li>Se estima que en los Estados Unidos hay 70,000 personas con Miastenia Gravis. </li></ul>
  8. 9. Miastenia Gravis <ul><li>En la persona joven predomina en la mujer </li></ul><ul><li>En la persona anciana predomina en el hombre. </li></ul>
  9. 10. Miastenia Gravis <ul><li>Es universal. </li></ul><ul><li>No es Hereditaria. </li></ul><ul><li>No es contagiosa. </li></ul><ul><li>No tiene preferencias estacionales. </li></ul><ul><li>Afecta todas las edades. </li></ul>
  10. 11. Unión neuromuscular
  11. 12. Edad de inicio 2a. y 3a. década en la mujer. 7a. y 8a. década en el hombre Los hombres son mas afectados que las mujeres.
  12. 13. Miastenia Gravis Datos Clínicos <ul><li>Debilidad. </li></ul><ul><li>B) Fatigabilidad. </li></ul>
  13. 14. Miastenia Gravis <ul><li>La debilidad es el síntoma cardinal de la Miastenia Gravis </li></ul>
  14. 16. Síntomas Iniciales <ul><li>Ptosis o diplopía en 2/3 de los pacientes </li></ul><ul><li>Dificultad para la masticación, deglución o para hablar en 1/6 de los pacientes. </li></ul><ul><li>En un 10% hay debilidad localizada </li></ul>
  15. 17. Miastenia Gravis <ul><li>La Pupila nunca se afecta en la Miastenia Gravis. </li></ul>
  16. 22. DEBILIDAD FATIGABLE
  17. 24. Crisis Miasténica <ul><li>La crisis ocurre cuando un paciente experimenta debilidad muscular que compromete la función respiratoria </li></ul><ul><li>Puede ser miasténica o colinérgica </li></ul><ul><li>Es una urgencia neurológica </li></ul>
  18. 26. Procedimientos Diagnósticos Prueba del Tensilón <ul><li>Es positiva en mas del 90% de los pacientes </li></ul><ul><li>Puede ser positiva en otras enfermedades </li></ul><ul><li>Precaución. Paciente hospitalizado. </li></ul><ul><li>Prueba de Neostigmina </li></ul>
  19. 28. Prueba de Tensilón <ul><li>Paciente hospitalizado </li></ul><ul><li>Canalizado.examen completo. Sv. </li></ul><ul><li>Atropina </li></ul><ul><li>Equipo de paro </li></ul>
  20. 29. Despues de tensilón Prueba de tensilón Antes de tensilón
  21. 30. Anticuerpos Antireceptores de acetilcolina <ul><li>Presentes </li></ul><ul><li>85% MG Generalizada. </li></ul><ul><li>55% MG ocular. </li></ul><ul><li>No predicen la severidad </li></ul><ul><li>Su presencia ante datos clínicos confirma el diagnóstico. </li></ul><ul><li>Su ausencia no excluye el Dx. </li></ul>
  22. 31. Procedimientos Diagnósticos Electromiografía. <ul><li>Estimulación repetitiva </li></ul><ul><li>EMG de fibra Única </li></ul>
  23. 32. Clasificación Clínica <ul><li>Generalizada </li></ul><ul><li>Neonatal </li></ul><ul><li>Congénita </li></ul><ul><li>Juvenil </li></ul><ul><li>Adulto leve, mod. y severa </li></ul><ul><li>Ocular - Juvenil y del Adulto </li></ul>
  24. 35. Steinert Kearn-sayre
  25. 36. tratamiento <ul><li>1.- anticolinesterásicos. </li></ul><ul><li>2.- esteroides. </li></ul><ul><li>3.- inmuno supresores. </li></ul><ul><li>4.- plasmaferesis </li></ul><ul><li>5.- inmunoglobulina. </li></ul><ul><li>6.- timectomia </li></ul>
  26. 37. Dosis equivalentes de anticolinesterasicos Dosis (mg) y vía Oral IM IV Jarabe Neostigmina 15 Neostigmina 1.5 0.5 Mestinon 60 2 0.7 60 mg 5 ml Mestinon Timespan 90 - 180 Ambenomio 7.5
  27. 38. Anticolinesterásicos toxicidad y efectos secundarios <ul><li>Muscarínicos </li></ul><ul><li>Músculo liso </li></ul><ul><li>Cólicos-diarrea </li></ul><ul><li>Nausea,vómito </li></ul><ul><li>Miosis pupilar </li></ul><ul><li>Broncoespasmo </li></ul><ul><li>Glandulas </li></ul><ul><li>Sialorrea,diaforesis </li></ul><ul><li>Nicotínicos </li></ul><ul><li>Musculoesqueletico s </li></ul><ul><li>Fasciculaciones </li></ul><ul><li>Espasmos musculares </li></ul><ul><li>debilidad </li></ul>
  28. 39. Glucocorticoides Efectos secundarios a largo plazo Gastrointestinales Nausea,vómitos, Gastritis, ulceras Dermatologicos ac né, hirsutismo Cushing Endocrino s: Hiperglucemia Hipokalemia . Inmunológicos : Inmunodepresión. Hematológicos : petequias Cardiovascular HAS edema Oftalmológicos : Cataratas Glaucoma Psicológicos: Depresión Insomnio. Otros: Aumento de peso
  29. 40. Azatioprina Efectos secundarios Gastrointestinales Nausea,vómitos,diarrea Ulceras,malestar Hematológicos Leucopenia, anemia Trombocitopenia. Hepático Enzimas Hepáticas elevadas Inmunológico Mayor susceptibilidad a infecciones Neoplásico Incrementa el riesgo para linfoma
  30. 41. Timectomia <ul><li>No se practica en la MG ocular. </li></ul><ul><li>No se realiza después de los 60 años (a menos que haya timoma). </li></ul><ul><li>Requiere preparación. </li></ul><ul><li>Mejores resultados en mujeres jóvenes. </li></ul><ul><li>Se prefiere abordaje transesternal. </li></ul>
  31. 42. TIMOMA
  32. 43. Terapias emergentes <ul><li>Micofenolato de mofedetilo </li></ul><ul><li>tacrolimus </li></ul>
  33. 45. El que alguien toque mi vida es un privilegio, Tocar la vida de alguien es un honor, Pero el ayudar a que otros toquen sus propias vidas Es un placer indescriptible!   Rubén Darío
  34. 51. Major Events in Neuromuscular Transmission <ul><li>Motor neuron depolarization causes action potential to travel down the nerve fiber to the neuromuscular junction (1). </li></ul><ul><li>Depolarization of the axon terminal causes an influx of Ca 2+ (2) which triggers fusion of the synaptic vesicles (3) and release of neurotransmitter ( Acetylcholine ; ACh) (4). </li></ul><ul><li>ACh diffuses across the synaptic cleft and binds to post-synaptic ACh receptor (AChR) located on the muscle fiber at the motor end-plate (5). </li></ul><ul><li>Binding of ACh to AChRs opens the channels causing an influx of Na (5), depolarization of the sarcolemma that travels down the t-tubules (6) and ultimately causes the release of Ca 2+ from the sarcoplasmic reticulum - CONTRACTION. </li></ul><ul><li>Unbound ACh in synaptic cleft defuses away or is hydrolyzed (inactivated) by acetylcholinesterase (AChE) (7). </li></ul>
  35. 52. Two main Types of Neuromuscular Blocking Drugs <ul><li>Nondepolarizing (competitive) </li></ul><ul><li>Depolarizing </li></ul>
  36. 53. Mechanism of Action of Nondepolarizing Neuromuscular Blocking Drugs
  37. 54. Non-depolarizing (competitive). <ul><li>Prototype of Non-depolarizing is tubo curarine (new generation: pancuronium and gallamine). </li></ul><ul><li>Mechanism of Action : In small clinical doses they act the predominantly at the nicotinic receptor site to block ACh. </li></ul><ul><li>At higher does they can block prejunctional Na channels thereby decreasing ACh release. </li></ul><ul><li>Because of the competitive nature of the postsynaptic blockade, transient relief of the block can be achieved by increasing ACh levels at the synaptic cleft (i.e. use cholinesterase inhibitors). </li></ul>
  38. 55. Nondepolarizing Agents <ul><li>Therapeutic Use: Adjuvant drugs in surgical anesthesia </li></ul><ul><li>Pharmacology: Must be given by injection because they are poorly absorbed orally. Do not cross the BBB. Generally excreted unchanged (i.e. not metabolized). </li></ul><ul><li>Adverse Effects: Tubocurarine causes release of histamine from mast cells – decrease in blood pressure, bronchospasms, skin wheals. Newer generation don’t. </li></ul>
  39. 56. <ul><li>Drug Interactions: </li></ul><ul><li>Cholinesterase Inhibitors decrease the effectiveness of nondepolarizing agents </li></ul><ul><li>Aminoglycoside antibiotics (e.g. streptomycin) decrease ACh release by competing with Ca 2+ – increase action of nondepolarizing drugs </li></ul><ul><li>Calcium channel blockers increase the actions of nondepolarizing drugs by decreasing the amount of ACh released (i.e. increase action of nondepolarizing drugs) </li></ul><ul><li>Halogenated carbon anesthetics (e.g. Isoflurane) enhance neuromuscular blockade by 1) decreasing excitability of motoneurons, 2) increasing muscle blood flow, and 3) decreased kinetics of AChRs (increase action of nondepolarizing drugs) </li></ul>
  40. 57. Depolarizing Agents
  41. 58. Depolarizing Agents <ul><li>Prototype of d epolarizing agent is succinylcholine (only depolarizing drug in clinical use). </li></ul><ul><li>Mechanism of Action : Similar action to ACh, but longer acting. </li></ul><ul><li>Phase 1 : Membrane is depolarized by opening AChR channels causing brief period of muscle fasciculation. </li></ul><ul><li>Phase II : End-plate eventually repolarizes, but because succinycholine is not metabolized like ACh it continues to occupy the AChRs to “desensitize” the end-plate. </li></ul><ul><li>Because of the mechanism of action of depolazing drugs is similar to ACh, their blocking effects are augmented by AChE inhibitors. </li></ul>
  42. 59. Depolarizing Agents <ul><li>Therapeutic Use: Adjuvant drugs in surgical anesthesia </li></ul><ul><li>Pharmacology: Duration of action is short (several minutes) because it is rapidly broken down by plasma cholinesterases (must be administered by continuous infusion) </li></ul><ul><li>Adverse Effects: When administered with halothane some genetically susceptible people (inherited autosomal dominant condition) experience malignant hyperthermia. Treatment: rapid cooling of the body and dantrolene </li></ul>
  43. 60. Cholinesterase Inhibitors
  44. 61. Cholinesterase Inhibitors <ul><li>Examples: Neostigmine, edrophonium. </li></ul><ul><li>Mechanism of Action : Inhibit acetylcholinesterase </li></ul><ul><li>Therapeutic Use: </li></ul><ul><li>Antidote for nondepolarizing blockers </li></ul><ul><li>Treatment of myasthenia gravis (neostigmine) </li></ul><ul><li>Diagnosis of myasthenia gravis (edrophonium) </li></ul>
  45. 62. Myasthenia Gravis                                                
  46. 63. Myasthenia Gravis is an autoimmune Disease that is characterized by a decrease in number of AChR Because there are fewer AChR to bind to the end plate potentials (EPPs) are smaller. With smaller EPPs the “ safety factor” is reduced there is less chance that the post-synaptic muscle fibres will be activated
  47. 64. Note: The amplitude of the end plate-potential is directly related to the amount of ACh that binds to the post-synaptic AChRs.
  48. 65. Myasthenia Gravis
  49. 66. <ul><li>Adverse Effects </li></ul><ul><li>Actions of generalized cholinergic activation (muscarinic and nicotinic). </li></ul><ul><li>Abdominal cramping </li></ul><ul><li>Diarrhea </li></ul><ul><li>Flushing (transient redness of the face and neck) </li></ul><ul><li>Increased salivation </li></ul><ul><li>Miosis (contraction of the pupils) </li></ul><ul><li>Incontinence </li></ul><ul><li>Bronchospasms (can exacerbate bronchial asthma) </li></ul>
  50. 67. Malignant Hyperthermia Dantrolene (interferes with EC coupling by decreasing Ca exflux from the SR
  51. 68. Diazepam (A Benzodiazepine that probably f acilitates the actions of GABA A in the CNS) Baclofen (GABA B agonist – note error in your handouts) Primarily used in the treatment of spastiticy associated with spinal cord injury Spasmolytic Drugs

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